Dementias affect at least 5-10% of the population over 65 years old, at least 20-30% of the population above the age of 85, and almost half of all patients in U.S. nursing homes (see Folstein, In: The Principles and Practice of Medicine, 21st Edition, Harvey, et al, Eds., Appleton-Century-Crofts, pages 379-385 (1984)), AD, which is the most common type of dementia, accounts for half of all diagnosed cases of dementia. The age of onset of AD ranges from 25 to 90 but usually occurs between 70 and 80. The clinical features of AD gradually include amnesia, aphasia, apraxia and agnosia, with death generally occurring 8-10 years after onset of the illness.
AD is generally diagnosed after exclusion of other causes of dementia. Clinical diagnosis of AD is typically only 75-90% correct and is normally verified only upon autopsy (see Davies, Neurobiol. Aging, 7:459-466 (1986)). In particular, in the early stages of the disorder, the diagnosis of AD and other dementias, such as multi-infarct dementia (MID) and Creutzfeldt-Jakob disease (CJD), is problematic. Not only is it difficult to distinguish these irreversible dementias from each other, but also, it is difficult to distinguish them from reversible dementia disorders, such as hypothyroidism, depression, hydrocephalus, brain tumors and thiamine deficiency. While physiologic testing, electroencephalography and computerized tomography are useful, they are non-specific diagnostic tools.
Although some types of dementia, e.g., those resulting from depression, nutritional disorders, and endocrine disorders, are curable, for most cases, including AD, MID, CJD and Huntington's disease (HD), there is at present no cure.
Brain levels of Mg are reduced in alcoholics, in comparison to non-alcoholics (see Zumkley, et al, Magnesium-Bull., 8:284-287 (1986)) and evidence indicates that alcohol-induced, long term Mg depletion is probably a prerequisite factor in human fatalities associated with cobalt toxicity resulting from cobalt-supplemented beer (see Marier, Magnesium-Bull., 8:293-296 (1986)). However, these observations have not previously been related to the pathogenesis of dementias.
It has been pointed out that brain ischemia or stroke-like events result in rapid neuronal losses of Mg and potassium (K), followed by uptake of sodium (Na) and calcium (Ca). Stroke patients are deficient in serum and CSF Mg levels. In experimental animals, acute Mg deficiency results in excess Ca uptake into the brain and in the occurrence of cerebrovasospasms. In clinical studies, infusion of Mg appears to alleviate cerebrovasospasms. Further, consumption of foods relatively high in Mg and K and low in Na appear to be associated with a lower than normal incidence of strokes (see Altura, et al, Magnesium, 3:195-211 (1984)). However, again, these observations have not previously been related to the pathogenesis of dementias.
Hypomagnesemic encephalopathy, which involves dementia, is correlated with low plasma Mg levels. This disorder is treatable with intramuscular administration of Mg, regardless of what led to the underlying Mg depletion (see Cohen, Magnesium, 4:203 (1985)). Heretofore, this type of disorder has not been suggested as one having an etiology, pathogenesis or response to treatment in common with most other dementias, including AD, MID, CJD and HD. These dementias are not characterized by low levels of Mg in plasma or CSF.
The increased incidence in the elderly of various chronic diseases associated with Mg depletion has been linked to insufficient daily intake of Mg, decreased intestinal absorption of Mg, and increased usage of pharmacologic agents which, as a side effect, enhance Mg excretion from the body (see Mountokalakis, Magnesium, 6:5-11 (1987)). However, these observations have not previously been related to the pathogenesis and possible treatment of dementias, as dementias generally have not been considered as diseases marked by an insufficiency of Mg.
On the other hand, Mg insufficiency may contribute to the progression of dementias, AD and HD are associated with an abnormally low level of g in brain neurons (see Korf, et al. Prog. Brain Res., 70:213-226 (1986)). However, Korf, et al. supra, did not view insufficiency of Mg as a key pathological event but, rather, as part of a pattern of cation changes in certain areas of the brain, including increases in intracellular Na and decreases in intracellular K. These cation changes were viewed as secondary to changes in neurotoxic and excitatory amino acids in brain cells of AD and HD patients.
AD and the amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam (ALS-PD) are associated with an abnormally high level of aluminum (Al) in brain neurons (see Perl, et al, Science, 208:297-299 (1980): Perl, et al, 217:1053-1055 (1982)). It has been suggested by the present inventor that the increased level of Al in the brain, which is associated with these dementias causes or contributes to an insufficiency of Mg since Al inhibits Mg-requiring enzymes.
In this connection, it has been hypothesized that increased levels of Ca in brain cells of aging rats are responsible for impairing learning (see Landfield, In: Treatment Development Strategies for Alzheimer's Disease, Crook, et al, Eds., Mark Powley Associates, pages 221-243, Madison, CT (1986)). Mg was administered as a Ca-blocking agent to aged rats, since Mg is a competitive inhibitor of the synaptic actions of Ca. However, these studies with aged rats have suggested to the present inventor a causal relationship involving an apparent deficiency of Mg in brain neurons and impaired maze reversal learning. i.e., treatment of the rats with Mg improves maze reversal learning. While it has been suggested that the level of Ca may be elevated in brain cells of AD patients, Korf, et al, supra, observed no changes in the level of brain levels of Ca, although decreases were seen in the brain levels of Mg, in AD and HD patients.